KRAS mutations are found in 40% of patients with metastatic colorectal cancer, but there has never been a drug to target them. However, among the many KRAS mutations, one particular mutation, KRAS G12C, is known to be present in 3-4% of patients with metastatic colorectal cancer, and an oral agent that targets it has recently been developed and shown to be effective.

A phase 2 clinical trial was conducted in metastatic colorectal cancer patients with KRAS G12C mutations treated with adagrasib monotherapy (600 mg orally twice daily) or in combination with adagrasib and intravenous cetuximab (400 mg loading dose per square meter of body surface area, followed by 250 mg weekly or 500 mg every 2 weeks).

As of June 16, 2022, a total of 44 patients had received ADAGRASIP, 32 of whom were treated with ADAGRASIP plus cetuximab. In the 43 evaluable patients in the monotherapy group, a response rate of 19% was reported, with a median progression-free survival of 5.6 months. In the 28 evaluable patients in the combination therapy group, a response rate of 46% was reported, with a median progression-free survival of 6.9 months. Overall survival was reported as 19.8 months in the adagrasip monotherapy group and 12.4 months in the combination group. Grade 3 or 4 treatment-related adverse events were reported in 34% of patients in the monotherapy group and 16% in the combination group, with no grade 5 events observed. Common grade 3 adverse events were anemia and diarrhea, which were controllable with dose adjustments and adjuvant therapy.

ADAGRASIP has demonstrated antitumor activity in several cancers harboring the KRAS G12C mutation, even in patients who have received multiple prior therapies. In patients with metastatic colorectal cancer with KRAS G12C mutations, both oral monotherapy and combination therapy with cetuximab demonstrated progression-free survival of >5 months, with adverse events reversible after drug discontinuation, and a low incidence of grade 3 or higher adverse events (16%), even in combination therapy.

A phase 3 trial is currently underway to evaluate the clinical effectiveness of adagrasip and cetuximab as a second-line agent after failure of first-line systemic antitumor therapy in patients with metastatic colorectal cancer harboring the KRAS G12C mutation.